The avian-origin H7N9 influenza virus that emerged in humans in China in 2013 presents a unique challenge to vaccine development because it is poorly immunogenic. Neutralizing antibodies are not detected in acute-phase infection. Anti-H7 antibody responses are significantly delayed and exhibit low avidity, in comparison with antibodies generated following seasonal influenza vaccination and infection. Furthermore, unadjuvanted H7N9 vaccines developed using conventional approaches elicit weak hemagglutinin-inhibition (HAI) antibody titers in clinical trials. Adjuvanted formulations may overcome this limitation but present significant regulatory challenges because adverse effects have recently been associated with adjuvanted influenza vaccines. Alternative vaccine approaches are needed to redress the low immunogenicity of H7N9 and circumvent safety risks. Because HAI titers are directly related to effector CD4+ T cell frequencies induced by vaccination, we hypothesize that a vaccine strategy that enhances effector CD4+ T cell activation will improve H7N9 vaccine efficacy without requiring adjuvant formulation. In published studies, we observed that the T cell epitope content of H7N9 virus differs significantly from more immunogenic influenza subtypes. H7N9 contains fewer T cell epitopes and some epitopes stimulate regulatory T cells (Tregs) that may help the virus evade effector responses needed for protection. These findings suggest that H7N9 vaccine design that carefully addresses the T cell subsets primed by immunization will overcome limitations of conventional vaccine approaches. The goal of this research program is to produce an unadjuvanted, influenza H7N9 virus-like particle (VLP) vaccine that augments effector CD4+ T cell responses and diminishes Treg effects for enhanced protection against disease. This new SBIR program will apply cutting edge computational and experimental methods that EpiVax has successfully applied against influenza and other viral and bacterial pathogens, as well as deep experience in influenza VLP production and vaccine testing in collaboration with Dr. Ted Ross at the University of Georgia. Two different engineered VLP strategies will be tested: (i) addition of effector epitopes and (ii) removal of Treg epitopes. Using these prototype effector T cell epitope-enhanced VLP vaccines in the proof-of-concept program described here, we will evaluate the vaccines for immunogenicity and efficacy and move forward in a Phase II program to further optimize efficacy and complete safety/toxicity studies in the run up to clinical trial.